title: Contribution of hydrophobic/hydrophilic modification on cationic chains of poly(ε-caprolactone)-graft-poly(dimethylamino ethylmethacrylate) amphiphilic co-polymer in gene delivery.
abstract: Nanoparticles (NPs) assembled from amphiphilic polycations have been certified as potential carriers for gene delivery. Structural modification of polycation moieties may be an efficient route to further enhance gene delivery efficiency. In this study two electroneutral monomers with different hydrophobicities, 2-hydroxyethyl methacrylate (HEMA) and 2-hydroxyethyl acrylate (HEA), were incorporated into the cationic poly(dimethylamino ethyl methacrylate) (PDMAEMA) side-chains of amphiphilic poly(ε-caprolactone)-graft-poly(dimethylamino ethylmethacrylate) (PCD) by random co-polymerization, to obtain poly(ε-caprolactone)-graft-poly(dimethylamino ethyl methacrylate-co-2-hydroxyethyl methacrylate) (PCD-HEMA) and poly(ε-caprolactone)-graft-poly(dimethylamino ethyl methacrylate-co-2-hydroxyethyl acrylate) (PCD-HEA). Minimal HEA or HEMA moieties in PDMAEMA do not lead to statistically significant changes in particle size, zeta potential, DNA condensation properties and buffering capacity of the naked NPs. However, the incorporation of HEMA and HEA lead to reductions and increases, respectively, in the surface hydrophilicity of the naked NPs and NPs/DNA complexes, which was confirmed by water contact angle assay. These simple modifications of PDMAEMA with HEA and HEMA moieties significantly affect the gene transfection efficiency on HeLa cells in vitro: PCD-HEMA NP/DNA complexes show a much higher transfection efficiency than PCD NPs/DNA complexes, while PCD-HEA NPs/DNA complexes show a lower transfection efficiency than PCD NP/DNA complexes. Fluorescence activated cell sorter and confocal laser scanning microscope results indicate that the incorporation of hydrophobic HEMA moieties facilitates an enhancement in both cellular uptake and endosomal/lysosomal escape, leading to a higher transfection efficiency. Moreover, the process of endosomal/lysosomal escape confirmed in our research that PCD and its derivatives do not just rely on the proton sponge mechanism, but also on membrane damage due to the polycation chains, especially hydrophobic modified ones. Hence, it is proved that hydrophobic modification of cationic side-chains is a crucial route to improve gene transfection mediated by polycation NPs.
authors.affiliation: School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, People's Republic of China.
authors.forename: Shangcong
authors.initials: S
authors.lastname: Han
authors.affiliation: Tianjin Life Science Research Center and Basic Medical School, Tianjin Medical University, Tianjin 300070, People's Republic of China.
authors.forename: Haiying
authors.initials: H
authors.lastname: Wan
authors.affiliation: School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, People's Republic of China.
authors.forename: Daoshu
authors.initials: D
authors.lastname: Lin
authors.affiliation: School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, People's Republic of China.
authors.forename: Shutao
authors.initials: S
authors.lastname: Guo
authors.affiliation: School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, People's Republic of China.
authors.forename: Hongxu
authors.initials: H
authors.lastname: Dong
authors.affiliation: School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, People's Republic of China.
authors.forename: Jianhua
authors.initials: J
authors.lastname: Zhang
authors.affiliation: School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, People's Republic of China.
authors.forename: Liandong
authors.initials: L
authors.lastname: Deng
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Life Sciences, Nankai University, Tianjin 300071, People's Republic of China.
authors.forename: Ruming
authors.initials: R
authors.lastname: Liu
authors.affiliation: Tianjin Life Science Research Center and Basic Medical School, Tianjin Medical University, Tianjin 300070, People's Republic of China. Electronic address: htang2002@yahoo.com.
authors.forename: Hua
authors.initials: H
authors.lastname: Tang
authors.affiliation: School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, People's Republic of China. Electronic address: ajdong@tju.edu.cn.
authors.forename: Anjie
authors.initials: A
authors.lastname: Dong
mesh_terms: D002412:Cations / Q000737:chemistry*; D016923:Cell Death; D004247:DNA / Q000378:metabolism; D004587:Electrophoresis, Agar Gel; D005453:Fluorescence; D018014:Gene Transfer Techniques; D006367:HeLa Cells; D006801:Humans; D057446:Hydrodynamics; D057927:Hydrophobic and Hydrophilic Interactions; D042541:Intracellular Space / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008689:Methacrylates / Q000737:chemistry*; D053758:Nanoparticles / Q000737:chemistry; D009757:Nylons / Q000737:chemistry*; D010316:Particle Size; D011091:Polyesters / Q000737:chemistry*; D011108:Polymers / Q000737:chemistry*; D055672:Static Electricity; D014162:Transfection; D014867:Water / Q000737:chemistry
chemical_list: D002412:Cations; D008689:Methacrylates; D009757:Nylons; D011091:Polyesters; D011108:Polymers; C407037:poly(2-(dimethylamino)ethyl methacrylate); D014867:Water; C016240:polycaprolactone; D004247:DNA
keywords: Cellular uptakes; Endosomal/lysosomal escape; Gene delivery; Hydrophobic modification